A liposome is a vesicle including phospholipids and their derivatives. It spontaneously forms a vesicle when phospholipids and their derivatives are dispersed in water, and has a characteristic of a lipid bilayer which includes an aqueous nucleus therewithin. Various liposomes have been used as carriers for drugs, enzymes, and therapeutic agents such as gene sequences in medical, pharmacy, and biochemistry fields.
Examples of liposome compositions are disclosed in U.S. Pat. Nos. 4,983,397; 6,476,068; 5,834,012; 5,756,069; 6,387,397; 5,534,241; 4,789,633; 4,925,661; 6,153,596; 6,057,299; 5,648,478; 6,723,338; 6,627,218; US Patent Publication Nos 2003/0224037; 2004/0022842; 2001/0033860; 2003/0072794; 2003/0082228; 2003/0212031; 2003/0203865; 2004/0142025; 2004/0071768; International Patent Publication Nos WO 00/74646; WO 96/13250; WO 98/33481; Papahadjopolulos D, Allen T M, Gbizon A, et al. “Sterically stabilized liposomes: Improvements in pharmacokinetics and antitumor therapeutic efficacy” Proc Natl Acad Sci U.S.A. (1991) 88: 11460-11464; Allen T M, Martin F J. “Advantages of liposomal delivery systems for anthracyclines” Semin Oncol (2004) 31: 5-15 (suppl 13). Weissig et al. Pharm. Res. (1998) 15: 1552-1556.
Various methods for preparing liposome have been known in the technical fields of the present invention, and some of them are described in detail in Liposome Technology 2nd Edition in G. Gregoriadis, CRC Press Inc., Boca Raton (1993).
In a case of these conventional liposome preparation technologies, it is possible to effectively prepare liposome at a small laboratory-scale manufacturing scale. However, the technologies have a large problem in that at a large commercial manufacturing scale, it is impossible to effectively mass-produce liposome due to some problems such as removal of an organic solvent used for dissolving phospholipids, and a size of a reactor for forming a lipid membrane.
As one of liposome preparing methods for commercial-scale mass-production, US Patent Publication No. 2004/0175417 discloses a method for preparing liposome, in which a complex of amphotericin B and phospholipids is formed in a mixed solution of oxidized chloroform and methanol, and then is spray-dried so as to provide lipid powder. However, this technology has a large problem in that high-boiling point solvents, such as dimethyacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), cannot be employed in a process because heated air is used for removing an organic solvent during a thy-spray process. The above mentioned solvents such as DMA, DMF and DMSO are generally known to sufficiently dissolve amphotericin B and maintain the stability of the dissolved amphotericin B.